The goal of the proposed investigation is to identify factors that influence the incidence of breast cancer in germline BRCA1/2 mutation carriers. The focus of the proposed study is to examine whether genetic factors involved in DNA damage and repair act as modifiers of BRCA1 and BRCA2. Our hypotheses are supported by findings that BRCA1 and BRCA2 are associated with protein complexes involved in various aspects of genome surveillance and repair and two recent studies reporting an interaction between a RAD51 polymorphism and BRCA2. We hypothesize that variants in the genes that encode proteins involved in DNA repair may interact with mutations in BRCA1 and BRCA2. A case-only design will be employed where cases are defined as women with breast cancer who have a known BRCA1/2 mutation status. The specific aims of this study are 1) to enroll approximately 1000 female patients diagnosed with breast cancer who have tested either positive or negative for a BRCA1 and BRCA2 mutation; 2) to assess gene-gene interactions between BRCA1/2 and polymorphisms in DNA damage and repair genes; and 3) to assess previously reported interactions between hormonally related genetic and environmental factors and BRCA1 and BRCA2 in a much larger dataset than in prior reports. Epidemiologic data and DNA will be collected for the analyses using instruments and methods developed in the context of a Cancer Genetic Network feasibility study. Women will be identified from clinic populations from 7 collaborating institutions. The molecular analyses for each of the genetic modifiers will be conducted at the Laboratory for Molecular Epidemiology by Dr. Timothy Rebbeck at the University of Pennsylvania. The Molecular and Cell Technology Core, directed by Dr. Jeffrey Marks, will perform genotyping and SNP discovery for genes involved in DNA damage and repair for which either the frequency of the polymorphism is not known or polymorphisms have yet to be identified that interact with BRCA1 and BRCA2. Innovative statistical methods will be employed to address the complex statistical issues related to examining modifiers in BRCA1 and BRCA2. The genetic epidemiology studies proposed here potentially could have profound ramifications in many areas related to the management of breast cancer including genetic counseling, prophylactic surgery, chemoprevention, and cancer therapeutics.